Amyloid Deposits: Protection Against Toxic Protein
Species?
The MIT Faculty has made this article openly available. Please share
how this access benefits you. Your story matters.
Citation
Treusch, Sebastian, Douglas M. Cyr, Douglas M., and Susan
Lindquist. "Amyloid Deposits: Protection Against Toxic Protein
Species?" Cell Cycle 8.11 (2009): 1668-1674.
As Published
http://www.landesbioscience.com/journals/6/article/8503/
Publisher
Landes Bioscience
Version
Author's final manuscript
Accessed
Wed May 25 18:18:09 EDT 2016
Citable Link
http://hdl.handle.net/1721.1/54770
Terms of Use
Attribution-Noncommercial-Share Alike 3.0 Unported
Detailed Terms
http://creativecommons.org/licenses/by-nc-sa/3.0/
Amyloid deposits: Protection against toxic protein species?
Sebastian Treusch1,2, Douglas M. Cyr3 and Susan Lindquist1,2*
1
Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA
02142;
2
Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute
of Technology, Cambridge, MA 02139
3
Department of Cell and Developmental Biology, School of Medicine, University of
North Carolina, Chapel Hill, NC 27599-7090;
*Correspondence to: Susan Lindquist, Whitehead Institute for Biomedical Research; 9
Cambridge Center; Cambridge; Massachusetts 02142 USA; Tel.: 617.258.5184; Email:
Lindquist_admin@wi.mit.edu
Keywords: neurodegenerative disease, amyloid formation, Alzheimer’s disease,
Huntington’s disease, Prion diseases, yeast prion, Rnq1
Abstract
Neurodegenerative diseases ranging from Alzheimer’s disease and polyglutamine
diseases to transmissible spongiform encephalopathies are associated with the
aggregation and accumulation of misfolded proteins. In several cases the intracellular and
extracellular protein deposits contain a fibrillar protein species called amyloid. However
while amyloid deposits are hallmarks of numerous neurodegenerative diseases, their
actual role in disease progression remains unclear. Especially perplexing is the often poor
correlation between protein deposits and other markers of neurodegeneration. As a result
the question remains whether amyloid deposits are the disease causing species, the
consequence of cellular disease pathology or even the result of a protective cellular
response to misfolded protein species. Here we highlight studies that suggest that
accumulation and sequestration of misfolded protein in amyloid inclusion bodies and
plaques can serve a protective function. Furthermore, we discuss how exceeding the
cellular capacity for protective deposition of misfolded proteins may contribute to the
formation of toxic protein species.
Introduction
The study of neurodegenerative diseases began over a hundred years ago when
Alois Alzheimer identified fibrillar structures within the postmortem brain of a patient
who had exhibited progressive cognitive dysfunction and psychosis1. It is now known
that the majority of neurodegenerative diseases characterized by progressive neuronal
dysfunction and loss are associated with the deposition of misfolded proteins. These
misfolded proteins are frequently found in a β-sheet rich fibrillar protein conformation
known as amyloid2, 3 (Figure 1). For more than forty years amyloid deposits were thought
to be causative agents in the degenerative process4. But the tables have turned. Recent
studies suggest instead that a group of still poorly defined pre-amyloid species, rather
than the amyloid deposits themselves, are the true toxic conformations 5-8 (Figure 1).
These soluble prefibrillar oligomers share conformational characteristics independent of
the proteins primary amino acid sequences and may share a common mechanism of
toxicity5. Indeed even proteins completely unrelated to disease, such as PI3 kinase and
the E. Coli protein HypF-N, can be induced to form such prefibrillar structures in vitro
and, when they do, they are toxic when applied extracellularly to cells in culture or
injected into rat brains9, 10. The intra- and extracellular conversion of misfolded proteins
into highly structured and less reactive amyloid forms may reduce the levels of these
toxic protein species and therefore be protective.
For the purpose of this perspective, we focus on three neurodegenerative diseases,
Alzheimer’s, Huntington’s and prion disease. We will first present studies in which the
formation of inclusion bodies and amyloid plaques protects against proteotoxicity and
then discuss how exceeding the cellular capacity for deposition of misfolded proteins
may give rise to toxic protein species. Although these studies do not preclude detrimental
effects of amyloid deposits in particular contexts (eg. obstructive vascular amyloid), they
clearly show that amyloid formation can be beneficial.
Pathological features associated with neurodegenerative diseases
The protein deposits found in Alzheimer’s, Huntington’s and prion disease are
formed by completely unrelated proteins. They accumulate in distinct brain regions and
have highly characteristic morphologies that form the basis of histological diagnosis.
Neurodegeneration also affects distinct regions of the brain in each diseases, reflecting
disease specific vulnerability of particular neurons11. However, in all three diseases the
correlation between the localization of neurodegeneration and protein deposition is weak.
Alzheimer’s disease (AD), the most common cause of dementia, most severely
affects the temporal pole, hippocampus and amygdala12. AD is characterized by the
accumulation of two very different proteins, each with a distinct distribution. Aβ
(amyloid β) peptide accumulates extracellularly in amyloid plaques while
hyperphosphorylated tau, a microtubule binding protein, accumulates intracellularly in
neurofibrillary tangles. A definitive pathological diagnosis of AD requires the detection
of both types of aggregation. Aβ may accumulate in different plaque forms. Neuritic
plaques, also referred to as classic or cored plaques, contain a dense amyloid core
surrounded in turn by a ring of abnormal cellular processes and a rim of diffuse
amyloid11, 12. In these neuritic plaques tau accumulation can also be present in dystrophic
neurites surrounding the amyloid core.
It has been hypothesized that Aβ accumulation is the primary cause of
pathogenesis in AD, yet there is a weak correlation between Aβ plaque density and the
severity of dementia11. For example, brain samples of aged patients without clinical
dementia can display abundant Aβ plaques11. To some extent this may be the
consequence of Aβ accumulating in plaques without any associated neuritic degeneration
(such as “burned-out” and “diffuse plaques”). Tau-containing neurofibrillary tangles
correlate better with clinical severity of AD than Aβ plaques, but even here, the question
remains whether tau aggregation itself is toxic or if it is the result of a protective
mechanism 13-16.
Huntington’s disease (HD), classified as a hyperkinetic movement disorder,
tends to affect brain regions distinct from those affected by Alzheimer’s disease. HD is
characterized by atrophy of the cerebral cortex, globus pallidus and striatum, specifically
with loss of medium spiny neurons within the neostriatum17-19. HD is caused by CAG
repeat expansions in the huntingtin gene, which lead to the accumulation of
polyglutamine-expanded Huntingtin protein within intranuclear inclusion bodies or
neurites11. The density of intranuclear inclusions correlates positively with the CAG
repeat length present in the huntingtin gene20. However neuronal vulnerability does not
correspond to the cellular concentration of Huntingtin protein nor the distribution of
Huntingtin inclusions21. In fact there is a distinct dissociation of inclusion distribution
and the selective pattern of striatal neuron loss, as few to no inclusions are detected in the
vulnerable striatal neurons22.
Prion diseases or spongiform encephalopathies can present in numerous ways,
such as sporadic versus variant Creutzfeldt-Jakob disease (CJD). While the prion disease
subtypes all involve the accumulation of a proteinase-K resistant form of the prion
protein PrP (PrPres), they each affect different brain regions and involve distinct patterns
of PrP aggregation11. Sporadic CJD causes spongiform change in the neuropil of the
cerebral cortex, subcortical grey matter and cerebellar molecular layer23. The brainstem
and spinal cord do not exhibit spongiform change although PrP deposits can be present.
PrPres deposits in sporadic CJD are found in synaptic, perivacuolar, perineuronal and
plaque-like patterns23. However neuronal loss correlates with microglial activation and
axonal damage, but not with local deposition of PrPres. In contrast, variant CJD, caused
by the consumption of meat from cows with Bovine Spongiform Encephalopathy, leads
to the presence of a large number of florid plaques in the cerbral and cerebellar cortex24.
Florid plaques have a dense amyloid core, a pale radiating fibrillar periphery and are
surrounded by a halo of spongiform change. Interestingly, spongiform change in variant
CJD is most pronounced in the basal ganglia, which contain relatively few amyloid
plaques24.
In summary, while the particular misfolded proteins vary in these diseases, in all
three cases protein deposits are a poor indicator of neuronal loss. This makes it plausible
that structured protein deposits help cells cope with misfolded proteins. In turn, the
failure of particular neurons to create such deposits may cause their disease specific
vulnerability.
Protein deposition as a cellular response to misfolded proteins
One of the first indications that protein inclusions may protect cells from toxic
misfolded proteins came from a study investigating the response of tissue culture cells to
either proteasome inhibitors or to overexpression of proteins targeted to the proteasome.
The Kopito laboratory established that exceeding the proteasome’s capacity to cope with
misfolded proteins, by either perturbation, leads to the accumulation of stable aggregates
at a distinct structure adjacent to the centrosome25. This structure was termed the
aggresome to emphasize that its formation is a common cellular response to the presence
of aggregated misfolded protein.
The aggresome is highly structured deposit of insoluble protein surrounded by a
cage formed by the intermediate filament protein vimentin. Most strikingly, aggresomes
are actively formed near the centrosome through dynein-dependent retrograde transport
of protein aggregates along microtubules25-27. Far from being amorphous protein
accumulations, aggresomes are formed through an active and conserved cellular process,
that appears to serve a vital purpose: sweeping the cytoplasm clear of potentially toxic
aggregates of misfolded proteins28.
Protein deposition as a protective mechanism
A host of studies involving proteins linked to neurodegenerative diseases and
other amyloidogenic proteins have investigated the role of inclusion and plaque
formation in pathogenicity. The case is perhaps strongest for Huntington’s disease, for
which it has been postulated that inclusions cause toxicity due to the sequestration of
proteins critical for cell homeostasis29. Indeed, inclusions formed by mutant Huntingtin
protein have been shown to sequester glyceraldehydes-3-phosphate dehydrogenase, to
impair transcription due to sequestration of the transcriptional coactivator CREB binding
protein, and to interfere with the function of the ubiquitin-proteasome system30-32.
However smaller oligomeric species and loosely packed amorphous aggregates may be
more prone to interact with and sequester proteins than densely packed amyloid deposits.
Indeed, several studies suggest that the formation of tightly packed Huntingtin
deposits is beneficial for cell survival. The Greenberg lab demonstrated that transfection
of mutant huntingtin into primary striatal neurons induced the formation of inclusions33.
The inclusions formed resembled protein deposits found in the brains of Huntington
patients, as they were intranuclear and ubiquitinylated. But inclusions were not sufficient
to induce apoptosis. On the contrary, inhibiting the ubiquitinylation of mutant Huntingtin
prevented the formation of inclusions and actually increased cell death33.
In a complementary study, the Finkbeiner group used time-lapse microscopy to
follow the fate of individual huntingtin transfected neurons. The majority of neurons died
without the formation of inclusion bodies and the formation of an inclusion body actually
increased the probability of neuron survival34. The formation of inclusion bodies directly
correlated with a decrease in soluble Huntingtin, suggesting that inclusion bodies protect
neurons by decreasing levels of soluble toxic isoforms of Huntingtin34. Inclusion body
formation could also serve a protective function by increasing the autophagic degradation
of the aggregated protein species35. Inclusions of mutant Huntingtin directly induce
autophagy through sequestration of mTOR, a negative regulator of autophagy, and
autophagy not only reduces the levels of aggregated but also soluble mutant huntingtin36,
37
.
Together, these studies suggest that compounds elevating the formation of
inclusion bodies, such as aggresomes, could lessen cellular pathology. On the other hand
compounds antagonizing the toxicity of mutant huntingtin by reducing its aggregation
have been identified38. On the surface, this appears to conflict with the notion that
promoting inclusions may be beneficial, but both, solubilization and inclusion body
formation, may diminish the levels of toxic oligomers, the more critical species in
pathogenesis. In fact, in a HD model a compound could prevent huntingtin-mediated
proteasome dysfunction by promoting inclusion formation39.
Although the characteristic protein deposits are found extracellularly in AD and
prion disease, not intracellularly as in HD, here too studies suggest that structured protein
deposits are less toxic than other conformers. As for HD, amyloid assembly may serve a
beneficial function by shifting the equilibrium away from more toxic conformers, such as
prefibrillar oligomers5, 6, 8.
In a collaborative effort, the Kelly and Dillin laboratories investigated the roles of
the aging process and the heat shock response in the formation of proteotoxic species in a
Caenorhabiditis elegans model of AD. The intracellular expression of Aβ resulted in the
formation of Aβ aggregates, but these aggregates did not correlate with toxicity40. RNAi
mediated repression of the insulin/IGF-1 receptor DAF-2, resulting in increased life span,
reduced Aβ-mediated toxicity while slightly increasing the amount of Aβ aggregates.
This protection depended on both daf-16 and hsf-1. Interestingly, repression of DAF-16
reduced the number of high molecular weight Aβ aggregates, while repression of HSF-1
increased it. The Kelly and Dillin laboratories concluded that two dichotomous cellular
pathways counteract Aβ toxicity: The HSF-1 pathway controls disaggregation, while the
DAF-16 pathway transforms toxic Aβ oligomers into larger Aβ aggregates of lower
toxicity40.
In a separate study by the Mucke group, a point mutation within Aβ, the Arctic
mutation (Aβ E22G), influenced the rate at which Aβ assembled into amyloid fibers. In
vitro and in transgenic mice, the Artic mutation enhanced formation of neuritic amyloid
plaques and diminished non-amyloid Aβ assemblies41. As non-amyloid Aβ assemblies
correlated with behavioral and neuronal deficits in these transgenic mice, the promotion
of Aβ amyloid fibril formation, without a coinciding increase in oligomeric Aβ, may be
beneficial.
Most recently, in a follow-up study of a clinical trial, the immunization of AD
patients with the full length Aβ peptide exhibited reduced Aβ immunostaining and
amyloid plaques42. Unfortunately, immunization neither slowed nor stopped the
progression of neurodegeneration. As immunization with Aβ peptide may not have
reduced the levels of toxic oligomeric Aβ species, the authors suggest, that immunization
specifically against oligomeric Aβ species may be more successful at halting
neurodegeneration.
Plaque formation may also prove beneficial in the case of prion disease. PrPres
isoforms, the protease resistant forms of PrP that include amyloid, are not toxic on their
own. Mice that do not express their own PrP protein (Prn-p0/0) are completely resistant to
the intracerebral injection of even very high doses PrPres43. Equally striking, mice
producing a secreted form of PrP, GPI anchor-less PrP, accumulated massive plaque-like
amyloid deposits, yet had no clinical manifestations of prion disease44. Some brain
lesions were present, but there was less neurodegeneration associated with these amyloid
plaques than with diffuse wild type PrPres deposits. These results were especially
significant as transgenic mice had up to 40% more PrPres in comparison to mice with
WT PrP44. Using human tissue samples, the Barron laboratory showed that the
accumulation of certain forms of PrPres failed to result in spongiform degeneration.
Brain extracts from two cases of familial prion disease were used to test the transmission
of disease to transgenic mice. One of the samples exhibited PrPres deposits and
spongiform change, while the other presented with PrPres deposits and no spongiform
change. Brain extract from the patient without spongiform degeneration did not result in
disease transmission but elicited PrPres deposition in large multicentric plaques.
Therefore, PrPres would appear to be rendered nonpathogenic by its sequestration in
amyloid plaques45.
Lessons from a yeast model
Yeast prion proteins, just as PrP, can adopt self-perpetuating conformational
states. In yeast, however, prions do not cause disease, but rather serve as heritable genetic
elements, perpetuated by the transfer of the prion template from mother to daughter
cells46. The heritable protein conformation of the yeast prions is amyloid in nature and, as
for Aβ, Huntingtin and PrP, amyloid formation by the yeast prion proteins proceeds
through intermediate oligomeric protein species47, 48. In fact, the observation that
prefibrillar oligomers are intermediates in amyloid formation was first made for the yeast
prion protein Sup3547, 49. Oligomers formed by the yeast prion protein Sup35 share
structural features with the oligomers formed by disease-related amyloidogenic proteins,
these include recognition by anti-oligomeric antibodies and interaction with specific
small compounds49, 50. Thus the study of yeast prions can provide insight into amyloid
formation and cellular responses to the presence of amyloid.
The yeast prion [RNQ+] is formed by the Rnq1 protein (The cytoplasmic
inheritance of yeast prions is designated by [ ]). Rnq is nonessential and has no known
biological function, except when it is in prion state51. In this case the [RNQ+] prion
interacts with other amyloidogenic proteins in vivo and enables them to adopt their
amyloid conformation. For example, [RNQ+] facilitates the de novo induction of the
[PSI+] prion state by enhancing the amyloid conversion of the yeast prion protein
Sup3552.
We recently reported that moderate ectopic overexpression of Rnq1 is extremely
toxic if endogenous Rnq1 is in the [RNQ+] prion conformation53. While overexpression
of Rnq1 did result in the formation of amyloid inclusions, as assessed by Thioflavin-T
staining, semi-denaturing agarose gels and in vitro seeding assays, the amyloid
conformation did not represent the toxic species. In fact, co-expression of an Hsp40
chaperone, Sis1, known to interact with the prion form of Rnq154, suppressed the toxicity
elicited by Rnq1 overexpression by promoting Rnq1 assembly into amyloid. Mutants of
Rnq1, impaired in their interaction with the chaperone and their ability to readily form
amyloid, exhibited enhanced toxicity. Chaperones have been shown to antagonize
toxicity associated with protein misfolding before, but in those cases overexpressed
chaperones either decreased protein aggregation55 or appeared to have no observable
effect on protein aggregation56. This study presents the first instance in which a
chaperone antagonizes the toxicity of a misfolding protein by facilitating its deposition
into an amyloid inclusion. It clearly demonstrates that actively promoting the formation
of inclusion bodies and even amyloid plaques may prove beneficial in protein misfolding
pathologies.
Formation of toxic protein species due to non-productive templating
While the formation of aggresomes and extracellular amyloid plaques appears to
serve a protective function, they could be associated with toxicity if their assembly is
overwhelmed by the amount of protein damage or impeded by other molecular and
cellular factors. As shown by the Kampinga group, aggresome formation by mutant
huntingtin in tissue culture cells did not affect the cellular progression through mitosis.
However, when the mutant huntingtin formed scattered secondary inclusions, the
completion of mitosis was delayed or even failed completely57. The Kampinga group
speculated that these secondary inclusions, distinct from aggresomes, form when the
process of aggresome formation is saturated57. These results are reminiscent of our
studies in which overexpression of the yeast prion protein Rnq1 resulted in toxicity when
it exceeded the cellular capacity to efficiently assemble the prion protein into amyloid.
The toxicity of Rnq1 overexpression was exacerbated by factors interfering with amyloid
assembly, such as repression of Sis1, the chaperone required for Rnq1 amyloid
formation, or mutations within Rnq1, which reduce its interaction with the chaperone53.
Importantly, Rnq1 overexpression only resulted in toxicity if the endogenous
Rnq1 protein was in its [RNQ+] prion conformation, making the otherwise benign prion
state a prerequisite for Rnq1 mediated toxicity. Interestingly, the Rnq1 prion state is also
required for toxicity of mutant huntingtin exon 1 in yeast models of Huntington’s
disease58. While the Rnq1 prion conformation usually acts as a template for the
conversion of soluble Rnq1 protein conformers into benign amyloid conformers, we
hypothesize that this process can also result in the formation of toxic protein species. We
refer to this as non-productive templating, which occurs when the cellular capacity to
facilitate amyloid formation is exceeded or impeded (Figure 2).
The notion of non-productive templating offers a unifying explanation for the
observation that amyloid formation is sometimes associated with toxicity even when the
amyloid form itself is benign. We discuss two cases in point: As mentioned earlier, the
expression of GPI-anchorless PrP resulted in the formation of amyloid plaques but was
not overtly toxic. However, when GPI-anchorless PrP was expressed together with WT
PrP, deposits of both amyloid and non-amyloid PrPres formed and the clinical
manifestations of scrapie disease were enhanced44. It has been suggested that PrPres
subverts a stress protective function of PrP into an apoptotic signal59. The toxic signal
elicited is dependent on the presence of PrPres and the expression of GPI-anchored PrP59.
PrPres may influence the folding state of the GPI-anchored PrP through incomplete
templating and thus cause the induction of a toxic signal.
The second case in point involves the fungal prion [Het-s]. Non-productive
templating can explain how the [Het-s] prion mediates heterokaryon incompatibility in
the fungus Podospora anserina60. Heterokaryon incompatability, a type of programmed
cell death, results when two cells with incompatible geneotypes, het-s and het-S, fuse to
form a mixed cytoplasm. The two alleles encode distinct sequence variants of the Het-s
protein. One, HET-s, is able to form the [Het-s] prion, where as the other, HET-S, cannot
adopt an amyloid conformation. The prion form of the HET-s allele by itself is
completely benign. However, if the HET-S allele is expressed in the presence of the [Hets] prion form it results in cell death. The interaction of HET-s protein with the [Het-s]
prion form leads to the templated formation of additional non-toxic prion amyloid. On the
other hand, we speculated that non-productive templating of the HET-S protein variant,
which cannot form amyloid, by the [Het-s] prion form leads to the formation of a toxic
misfolded species resulting in cell death (Figure 2).
Conclusions
The protein deposits that are the hallmark of neurodegenerative diseases are now
seen in a different light. Formerly viewed as the cause of cellular dysfunction and
neuronal loss, intracellular protein deposits, especially, are the product of a regulated
cellular process enabling cells to cope with the accumulation of misfolded and damaged
proteins. This notion is supported by studies demonstrating that the deposition of
damaged and misfolded proteins in inclusions enables mitotic cells, ranging from the
unicellular organism Escherichia coli to human embryonic stem cells, to asymmetrically
segregate the accumulated damage to the daughter cell with the shorter life expectancy57,
61-64
. Based on our results in yeast, we suggest that inefficiencies in inclusion body and
plaque formation, arising with accumulating protein damage, can result in the inception
of toxic protein species due to non-productive templating. Further studies are needed to
elucidate which types of protein deposits in the individual diseases are protective and
how their formation circumvents the formation of more toxic species, such as prefibrillar
oligomers.
Acknowledgements
We would like to thank Peter Douglas, Vikram Khurana, Kent Matlack and Chris
Pacheco for critical reading of the manuscript. We also thank Tom DiCesare for help
with the illustrations. This work was supported by the National Institutes of Health
(D.M.C. and S.L.) and a Howard Hughes Medical Institute Investigatorship (to S.L.).
1.
Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English
translation of Alzheimer's 1907 paper, "Uber eine eigenartige Erkankung der Hirnrinde".
Clin Anat 1995; 8:429-31.
2.
Nelson R, Sawaya MR, Balbirnie M, Madsen AO, Riekel C, Grothe R, Eisenberg
D. Structure of the cross-beta spine of amyloid-like fibrils. Nature 2005; 435:773-8.
3.
Caughey B, Lansbury PT. Protofibrils, pores, fibrils, and neurodegeneration:
separating the responsible protein aggregates from the innocent bystanders. Annu Rev
Neurosci 2003; 26:267-98.
4.
Roth M, Tomlinson BE, Blessed G. Correlation between scores for dementia and
counts of 'senile plaques' in cerebral grey matter of elderly subjects. Nature 1966;
209:109-10.
5.
Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe
CG. Common structure of soluble amyloid oligomers implies common mechanism of
pathogenesis. Science 2003; 300:486-9.
6.
Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe
KH. A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006;
440:352-7.
7.
Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett
FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe
DJ. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair
synaptic plasticity and memory. Nat Med 2008; 14:837-42.
8.
Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ,
Selkoe DJ. Naturally secreted oligomers of amyloid beta protein potently inhibit
hippocampal long-term potentiation in vivo. Nature 2002; 416:535-9.
9.
Baglioni S, Casamenti F, Bucciantini M, Luheshi LM, Taddei N, Chiti F, Dobson
CM, Stefani M. Prefibrillar amyloid aggregates could be generic toxins in higher
organisms. J Neurosci 2006; 26:8160-7.
10.
Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N,
Ramponi G, Dobson CM, Stefani M. Inherent toxicity of aggregates implies a common
mechanism for protein misfolding diseases. Nature 2002; 416:507-11.
11.
Ellison D, Love S, Chimelli L, Harding BN, Lowe J, Vinters HV.
Neuropathology: A reference text of CNS pathology. St Louis: MOSBY, 2004.
12.
Duyckaerts C, Dickson D. Neuropathology of Alzheimer's Disease. In: Dickson
D, ed. Neurodegeneration: The Molecular Pathology of Dementia and Movement
Disorders. Basel: ISN Neuropath Press, 2003:47-65.
13.
Hernandez F, Avila J. Tau aggregates and tau pathology. J Alzheimers Dis 2008;
14:449-52.
14.
Gotz J, Ittner LM, Fandrich M, Schonrock N. Is tau aggregation toxic or
protective: a sensible question in the absence of sensitive methods? J Alzheimers Dis
2008; 14:423-9.
15.
Congdon EE, Duff KE. Is tau aggregation toxic or protective? J Alzheimers Dis
2008; 14:453-7.
16.
Bretteville A, Planel E. Tau aggregates: toxic, inert, or protective species? J
Alzheimers Dis 2008; 14:431-6.
17.
Ross CA. Introduction to Trinucleotide Repeat Disorders. In: Dickson D, ed.
Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders.
Basel: ISN Neuropath Press, 2003:226-8.
18.
Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration. Annu Rev
Neurosci 2000; 23:217-47.
19.
Cummings CJ, Zoghbi HY. Trinucleotide repeats: mechanisms and
pathophysiology. Annu Rev Genomics Hum Genet 2000; 1:281-328.
20.
Hedreen JC, Roos RAC. Huntington's Disease. In: Dickson D, ed.
Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders.
Basel: ISN Neuropath Press, 2003:229-41.
21.
Gutekunst CA, Li SH, Yi H, Mulroy JS, Kuemmerle S, Jones R, Rye D, Ferrante
RJ, Hersch SM, Li XJ. Nuclear and neuropil aggregates in Huntington's disease:
relationship to neuropathology. J Neurosci 1999; 19:2522-34.
22.
Kuemmerle S, Gutekunst CA, Klein AM, Li XJ, Li SH, Beal MF, Hersch SM,
Ferrante RJ. Huntington aggregates may not predict neuronal death in Huntington's
disease. Ann Neurol 1999; 46:842-9.
23.
Budka H, Head MW, Ironside JW, Gambetti P, Parchi P, Zeidler M, Tagliavini F.
Sporadic Creutzfeldt-Jakob Disease. In: Dickson D, ed. Neurodegeneration: The
Molecular Pathology of Dementia and Movement Disorders. Basel: ISN Neuropath Press,
2003:287-97.
24.
Ironside JW, Head MW, Will RG. Variant Creutzfeldt-Jakob Disease. In: Dickson
D, ed. Neurodegeneration: The Molecular Pathology of Dementia and Movement
Disorders. Basel: ISN Neuropath Press, 2003:310-7.
25.
Johnston JA, Ward CL, Kopito RR. Aggresomes: a cellular response to misfolded
proteins. J Cell Biol 1998; 143:1883-98.
26.
Garcia-Mata R, Bebok Z, Sorscher EJ, Sztul ES. Characterization and dynamics
of aggresome formation by a cytosolic GFP-chimera. J Cell Biol 1999; 146:1239-54.
27.
Johnston JA, Illing ME, Kopito RR. Cytoplasmic dynein/dynactin mediates the
assembly of aggresomes. Cell Motil Cytoskeleton 2002; 53:26-38.
28.
Kopito RR. Aggresomes, inclusion bodies and protein aggregation. Trends Cell
Biol 2000; 10:524-30.
29.
Preisinger E, Jordan BM, Kazantsev A, Housman D. Evidence for a recruitment
and sequestration mechanism in Huntington's disease. Philos Trans R Soc Lond B Biol
Sci 1999; 354:1029-34.
30.
Burke JR, Enghild JJ, Martin ME, Jou YS, Myers RM, Roses AD, Vance JM,
Strittmatter WJ. Huntingtin and DRPLA proteins selectively interact with the enzyme
GAPDH. Nat Med 1996; 2:347-50.
31.
Nucifora FC, Jr., Sasaki M, Peters MF, Huang H, Cooper JK, Yamada M,
Takahashi H, Tsuji S, Troncoso J, Dawson VL, Dawson TM, Ross CA. Interference by
huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity.
Science 2001; 291:2423-8.
32.
Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome
system by protein aggregation. Science 2001; 292:1552-5.
33.
Saudou F, Finkbeiner S, Devys D, Greenberg ME. Huntingtin acts in the nucleus
to induce apoptosis but death does not correlate with the formation of intranuclear
inclusions. Cell 1998; 95:55-66.
34.
Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S. Inclusion body
formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature
2004; 431:805-10.
35.
Taylor JP, Tanaka F, Robitschek J, Sandoval CM, Taye A, Markovic-Plese S,
Fischbeck KH. Aggresomes protect cells by enhancing the degradation of toxic
polyglutamine-containing protein. Hum Mol Genet 2003; 12:749-57.
36.
Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F,
Easton DF, Duden R, O'Kane CJ, Rubinsztein DC. Inhibition of mTOR induces
autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of
Huntington disease. Nat Genet 2004; 36:585-95.
37.
Williams A, Sarkar S, Cuddon P, Ttofi EK, Saiki S, Siddiqi FH, Jahreiss L,
Fleming A, Pask D, Goldsmith P, O'Kane CJ, Floto RA, Rubinsztein DC. Novel targets
for Huntington's disease in an mTOR-independent autophagy pathway. Nat Chem Biol
2008; 4:295-305.
38.
Ehrnhoefer DE, Duennwald M, Markovic P, Wacker JL, Engemann S, Roark M,
Legleiter J, Marsh JL, Thompson LM, Lindquist S, Muchowski PJ, Wanker EE. Green
tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and
reduces toxicity in Huntington's disease models. Hum Mol Genet 2006; 15:2743-51.
39.
Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT, McLean
PJ, Young AB, Housman DE, Kazantsev AG. Pharmacological promotion of inclusion
formation: a therapeutic approach for Huntington's and Parkinson's diseases. Proc Natl
Acad Sci U S A 2006; 103:4246-51.
40.
Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A. Opposing activities
protect against age-onset proteotoxicity. Science 2006; 313:1604-10.
41.
Cheng IH, Scearce-Levie K, Legleiter J, Palop JJ, Gerstein H, Bien-Ly N,
Puolivali J, Lesne S, Ashe KH, Muchowski PJ, Mucke L. Accelerating amyloid-beta
fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse
models. J Biol Chem 2007; 282:23818-28.
42.
Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones
RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42
immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled
phase I trial. Lancet 2008; 372:216-23.
43.
Bueler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M, Weissmann C.
Mice devoid of PrP are resistant to scrapie. Cell 1993; 73:1339-47.
44.
Chesebro B, Trifilo M, Race R, Meade-White K, Teng C, LaCasse R, Raymond
L, Favara C, Baron G, Priola S, Caughey B, Masliah E, Oldstone M. Anchorless prion
protein results in infectious amyloid disease without clinical scrapie. Science 2005;
308:1435-9.
45.
Piccardo P, Manson JC, King D, Ghetti B, Barron RM. Accumulation of prion
protein in the brain that is not associated with transmissible disease. Proc Natl Acad Sci
U S A 2007; 104:4712-7.
46.
Shorter J, Lindquist S. Prions as adaptive conduits of memory and inheritance.
Nat Rev Genet 2005; 6:435-50.
47.
Serio TR, Cashikar AG, Kowal AS, Sawicki GJ, Moslehi JJ, Serpell L, Arnsdorf
MF, Lindquist SL. Nucleated conformational conversion and the replication of
conformational information by a prion determinant. Science 2000; 289:1317-21.
48.
Chiti F, Dobson CM. Protein misfolding, functional amyloid, and human disease.
Annu Rev Biochem 2006; 75:333-66.
49.
Shorter J, Lindquist S. Hsp104 catalyzes formation and elimination of selfreplicating Sup35 prion conformers. Science 2004; 304:1793-7.
50.
Wang H, Duennwald ML, Roberts BE, Rozeboom LM, Zhang YL, Steele AD,
Krishnan R, Su LJ, Griffin D, Mukhopadhyay S, Hennessy EJ, Weigele P, Blanchard BJ,
King J, Deniz AA, Buchwald SL, Ingram VM, Lindquist S, Shorter J. Direct and
selective elimination of specific prions and amyloids by 4,5-dianilinophthalimide and
analogs. Proc Natl Acad Sci U S A 2008; 105:7159-64.
51.
Sondheimer N, Lindquist S. Rnq1: an epigenetic modifier of protein function in
yeast. Mol Cell 2000; 5:163-72.
52.
Derkatch IL, Bradley ME, Hong JY, Liebman SW. Prions affect the appearance
of other prions: the story of [PIN(+)]. Cell 2001; 106:171-82.
53.
Douglas PM, Treusch S, Ren HY, Halfmann R, Duennwald ML, Lindquist S, Cyr
DM. Chaperone-dependent amyloid assembly protects cells from prion toxicity. Proc
Natl Acad Sci U S A 2008; 105:7206-11.
54.
Sondheimer N, Lopez N, Craig EA, Lindquist S. The role of Sis1 in the
maintenance of the [RNQ+] prion. Embo J 2001; 20:2435-42.
55.
Cummings CJ, Mancini MA, Antalffy B, DeFranco DB, Orr HT, Zoghbi HY.
Chaperone suppression of aggregation and altered subcellular proteasome localization
imply protein misfolding in SCA1. Nat Genet 1998; 19:148-54.
56.
Warrick JM, Chan HY, Gray-Board GL, Chai Y, Paulson HL, Bonini NM.
Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the
molecular chaperone HSP70. Nat Genet 1999; 23:425-8.
57.
Rujano MA, Bosveld F, Salomons FA, Dijk F, van Waarde MA, van der Want JJ,
de Vos RA, Brunt ER, Sibon OC, Kampinga HH. Polarised asymmetric inheritance of
accumulated protein damage in higher eukaryotes. PLoS Biol 2006; 4:e417.
58.
Meriin AB, Zhang X, He X, Newnam GP, Chernoff YO, Sherman MY.
Huntington toxicity in yeast model depends on polyglutamine aggregation mediated by a
prion-like protein Rnq1. J Cell Biol 2002; 157:997-1004.
59.
Rambold AS, Muller V, Ron U, Ben-Tal N, Winklhofer KF, Tatzelt J. Stressprotective signalling of prion protein is corrupted by scrapie prions. Embo J 2008;
27:1974-84.
60.
Coustou-Linares V, Maddelein ML, Begueret J, Saupe SJ. In vivo aggregation of
the HET-s prion protein of the fungus Podospora anserina. Mol Microbiol 2001; 42:132535.
61.
Erjavec N, Larsson L, Grantham J, Nystrom T. Accelerated aging and failure to
segregate damaged proteins in Sir2 mutants can be suppressed by overproducing the
protein aggregation-remodeling factor Hsp104p. Genes Dev 2007; 21:2410-21.
62.
Lindner AB, Madden R, Demarez A, Stewart EJ, Taddei F. Asymmetric
segregation of protein aggregates is associated with cellular aging and rejuvenation. Proc
Natl Acad Sci U S A 2008; 105:3076-81.
63.
Aguilaniu H, Gustafsson L, Rigoulet M, Nystrom T. Asymmetric inheritance of
oxidatively damaged proteins during cytokinesis. Science 2003; 299:1751-3.
64.
Fuentealba LC, Eivers E, Geissert D, Taelman V, De Robertis EM. Asymmetric
mitosis: Unequal segregation of proteins destined for degradation. Proc Natl Acad Sci U
S A 2008; 105:7732-7.
Figure Legends
Figure 1) Aggregation of misfolded protein can give rise to oligomers, amorphous
aggregates and inclusion bodies.
The accumulation of misfolded protein leads to the formation of different protein
assemblies. Prefibrillar oligomers formed by different proteins share a common structure
and are thought to be the toxic protein species in diseases such as Alzheimer’s and
Huntington’s5, 6. Oligomers are conformationaly molten and can associate to form
amorphous aggregates or convert to an amyloidogenic nucleus to initiate amyloid fibril
formation. Amyloid fibrils have a highly organized structure due to repeating β-sheets
and are insoluble. Amyloid fibrils are often found in intra- and extracellular inclusions
such as inclusion bodies and amyloid plaques. The generation of amyloid fibers and
inclusion bodies can protect cells by reducing the formation of highly interactive toxic
oligomers and amorphous aggregates.
Figure 2) Amyloid and Non-productive templating
Amyloid fibrils grow by causing protein of the same amino-acid sequence to adopt the
same amyloid conformation. This is referred to as amyloid templating and involves the
efficient addition of monomer or oligomeric species to the amyloid fiber, which maybe
assisted by specific chaperones (e.g. Rnq1 and the Hsp40 Sis1, Sup35NM and Hsp10449).
If the amount of substrate exceeds the cellular capacity for amyloid conversion or if
amino acid sequences are incompatible, the interaction with the amyloid fibrils may give
rise to other abnormal conformational species, which may go on to form toxic oligomers
and amorphous aggregates (Rnq1, PrP and Het-s/S). We refer to this as non-productive
templating.